This project will test the specificity of cortico-cerebellar-thalamic-cortical circuit (CCTCC)/cognitive dysmetria construct by comparing patients with schizophrenia to healthy volunteer subjects. This construct proposes that schizophrenia is characterized by an underlying dysfunction of the neural circuits that provide interconnections and ongoing feedback between key cortical regions and the cerebellum, linked through the thalamus. We refer to this circuit as the CCTCC. This relatively novel model emphasizes the importance of studying connectivity in schizophrenia, in addition to regional cortical abnormalities, and it stresses that the cerebellum plays a key role in both normal cognition and in the cognitive and symptomatic disturbances observed in schizophrenia. A malfunctioning CCTCC produces a fundamental cognitive deficit, which we refer to as a "cognitive dysmetria." In the healthy brain, the CCTCC facilitates the fluid coordination of mental functions-planning, initiation, timing and monitoring of behavior. Patients with schizophrenia display impairments in both cognitive and motor behavior that reflect a dysfunction in this circuitry. Our interest in the CCTCC, and particularly in subcortical regions (i.e., thalamus and cerebellum), is based on considerable empirical work conducted during the previous funding period of this anatomic MR grant, as well as our functional imaging studies. Basically, we have observed consistent functional and anatomic abnormalities in thalamus and cerebellum: We have also amassed evidence for white matter abnormalities in schizophrenia-the substrate of connectivity. It is also based on the pioneering viral tract-tracing studies conducted during the past decade, primarily by Peter Strick, which demonstrate closed cortical-cerebellar-thalamic-cortical feedback loops between "high cortical regions" (e.g., frontal and parietal cortex), which suggest that the cerebellum is likely to be playing a role in "higher cortical functions." Therefore, we propose to continue to explore the role of the CCTCC in schizophrenia. The proposed studies will build on our previous methodological advances in the use of anatomic MR, which has provided us with a powerful array of reliable and well-validated tools for measuring a variety of brain regions in a relatively rapid and automated way. We propose to use these tools in the current project, complemented with two new methods: structural equation modelling (SEM) and diffusion tensor imaging (DTI). These two approaches will provide convergent methods for comparing the CCTCC in patients with schizophrenia and healthy volunteers. We will compare our CCTCC model to an alternative model that is widely hypothesized to be important, the Cortical-Striatal-Thalamic circuit (CST), which will assist us in further testing our hypothesis that cerebellar malfunction (within a circuit model) contributes to the manifestations of schizophrenia. In addition, we will explore the CCTCC/cognitive dysmetria model using a group of experimental "cognitive dysmetria tests" designed to assess the various functions mediated by the CCTCC, such as timing or eyeblink conditioning, as well as several control experimental tasks. The control tasks were chosen in order to address the "generalized deficit problem." These are tasks that patients with schizophrenia are able to do at a normal or superior level. This group of tasks will give us an additional test of the specificity of the CCTCC/cognitive dysmetria construct.